Project Summary: Apathy is a common motivational alteration in HIV-1+ individuals, affecting between 30-60% of the population, despite antiretroviral therapy. The high prevalence of apathy in HIV-1+ individuals is one of the biggest challenges facing HIV clinicians and researchers alike; there is a critical need to develop treatment approaches for HAND. Using the HIV-1 transgenic (Tg) rat model in a prospective longitudinal design, we will test the hypothesis that the development and progression of dysregulation of motivational processes associated with HIV-1 are consequent to synaptodendritic pathology, neuroinflammation and oxidative stress of the dopamine (DA) system in the prefrontal cortex-basal ganglia axis, and that the trajectory of motivational dysregulation will be altered with a therapeutic approach targeted to the mesocorticolimbic DA system. The specific aims are: 1) To establish the development and progression of motivational dysregulation in the HIV-1 Tg rat as measured with drug, food, and natural reinforcers, as distinct from potential changes in sensory and activity confounds. The progression of neurocognitive dysfunction will be assessed with periodic tests from pre-adolescence through advanced age, given the exponential growth of 65+ year old HIV+ patients. Both males and females will be examined. 2) To establish the progression of CNS synaptodendritic pathology in the prefrontal cortex (PFC) and medium spiny neurons (MSN) of the nucleus accumbens of the HIV-1 Tg rat with a focus on quantifying dendritic branching and spine parameter alterations. Specifically, synaptodendritic complexity, neuroinflammation, and oxidative stress will be assessed in different cohorts as the basis of the dysregulation of motivational processes. 3) To establish the treatment of the dysregulation of motivational processes consequent to chronic, low-level inflammation and HIV-1 protein exposure with currently used agonists or antagonists, or novel agents, targeted to the identified DA system dysfunction. With currently used agonists or antagonists, or novel agents, targeted to the identified DA system dysfunction we will mechanistically test the functional role of the neurobiological changes in the DA receptors and dopamine transporter (DAT) as a neurochemical mechanism contributing to, if not mediating, the motivational dysregulation consequent to chronic expression of the HIV-1 transgene. Initially we will establish the optimal therapeutic window. These studies will establish the functional role of alterations in synapto- dendritic complexity, neuroinflammation and oxidative stress as neurobiological mechanisms contributing to, if not mediating, the dysregulation of motivational systems consequent to chronic expression of the HIV-1 transgene. The program goal of our longitudinal studies is to establish our ability to predict motivational dysregulation as a function of chronic expression of the HIV-1 transgene, to provide a greater mechanistic understanding of the interrelationships of HIV-1-induced apathy and DA system dysfunction, and to improve the therapeutic options relevant to HIV-1+ individuals and improve their quality of life.